Cleaved Caspase-3 Transcriptionally Regulates Angiogenesis-Promoting Chemotherapy Resistance
Cleaved Caspase-3 Transcriptionally Regulates Angiogenesis-Promoting Chemotherapy Resistance
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DOI：
10.1158/0008-5472.can-19-0840
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发表时间：
2019-12-01
期刊：
影响因子：
11.2
通讯作者：
Boidot, Romain
中科院分区：
文献类型：
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作者：
Bernard, Antoine;Chevrier, Sandy;Boidot, Romain
半胱天冬酶在细胞凋亡中的作用是众所周知的。最近，半胱天冬酶的非凋亡作用已被确定，然而，这些非经典的作用没有得到很好的记录，所涉及的机制并不完全清楚。在这里，我们使用人类和小鼠熟练的caspase-3癌细胞系和人类缺陷的caspase-3癌细胞研究了切割的caspase-3的作用。切割型caspase-3作为转录因子直接与DNA结合。在caspase-3的小亚基中鉴定了DNA结合结构域，并且活性构象对于caspase-3的转录活性是必需的。Caspase-3 DNA结合通过上调促血管生成基因的表达和激活促进内皮细胞活化的途径来增强血管生成。一些促凋亡基因在caspase-3-proficient细胞中下调。抑制半胱天冬酶-3增加了化疗的疗效，并减少了自发性肿瘤的发展。这些数据突出了一个新的非凋亡的caspase-3的作用，并表明，裂解的caspase-3可能是一个新的治疗cancer.Significance目标：这些研究结果报告的caspase-3的非经典功能，通过证明其转录调节VEGFR途径的能力。
Caspases are well known for their role in apoptosis. Recently, nonapoptotic roles of caspases have been identified, however, these noncanonical roles are not well documented and the mechanisms involved are not fully understood. Here, we studied the role of cleaved caspase-3 using human- and mouse-proficient caspase-3 cancer cell lines and human-deficient caspase-3 cancer cells. Cleaved caspase-3 functioned as a transcription factor and directly bound to DNA. A DNA-binding domain was identified in the small subunit of caspase-3 and an active conformation was essential for caspase-3 transcriptional activity. Caspase-3 DNA binding enhanced angiogenesis by upregulating the expression of proangiogenic genes and by activating pathways that promoted endothelial cell activation. Some proapoptotic genes were downregulated in caspase-3-proficient cells. Inhibiting caspase- 3 increased the efficacy of chemotherapy and decreased spontaneous tumor development. These data highlight a novel nonapoptotic role of caspase-3 and suggest that cleaved caspase-3 could be a new therapeutic target in cancer.Significance: These findings report a noncanonical function of caspase-3 by demonstrating its ability to transcriptionally regulate the VEGFR pathway.